Abstract

Background

Artemisinin monotherapy of Plasmodium falciparum infection is frequently ineffective due to recrudescence. Artemisinin-induced dormancy, shown in vitro and in animal models, provides a plausible explanation. To date, direct evidence of artemisinin-induced dormancy in humans is lacking.

Methods

Blood samples were collected from Plasmodium falciparum 3D7- or K13-infected participants before and 48–72 hours after single-dose artesunate (AS) treatment. Parasite morphology, molecular signature of dormancy, capability and dynamics of seeding in vitro cultures, and genetic mutations in the K13 gene were investigated.

Results

Dormant parasites were observed in post-AS blood samples of 3D7- and K13-infected participants. The molecular signature of dormancy, an up-regulation of acetyl CoA carboxylase, was detected in 3D7 and K13 samples post-AS, but not in pre-AS samples. Posttreatment samples successfully seeded in vitro cultures, with a significant delay in time to reach 2% parasitemia compared to pretreatment samples.

Conclusions

This study provides strong evidence for the presence of artemisinin-induced dormant parasites in P. falciparum infections. These parasites are a likely reservoir for recrudescent infection following artemisinin monotherapy and artemisinin combination therapy (ACT). Combination regimens that target dormant parasites or remain at therapeutic levels for a sufficient time to kill recovering parasites will likely improve efficacy of ACTs.

中文翻译：

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青蒿琥酯治疗后人类感染中的休眠恶性疟原虫寄生虫

摘要

背景

恶性疟原虫感染的青蒿素单药治疗由于复发而经常无效。在体外和动物模型中显示的青蒿素诱导的休眠提供了一个合理的解释。迄今为止，缺乏青蒿素诱导人类休眠的直接证据。

方法

在单剂量青蒿琥酯 (AS) 治疗之前和之后 48-72 小时从感染恶性疟原虫3D7 或 K13 的参与者收集血液样本。研究了寄生虫形态、休眠的分子特征、体外培养的播种能力和动力学以及 K13 基因的基因突变。

结果

在 3D7 和 K13 感染参与者的 AS 后血液样本中观察到休眠寄生虫。在 AS 后的 3D7 和 K13 样品中检测到休眠的分子特征，即乙酰 CoA 羧化酶的上调，但在 AS 前的样品中未检测到。与预处理样本相比，处理后样本成功地接种了体外培养物，达到 2% 寄生虫血症的时间显着延迟。

结论

这项研究为恶性疟原虫感染中存在青蒿素诱导的休眠寄生虫提供了强有力的证据。这些寄生虫可能是青蒿素单药治疗和青蒿素联合治疗 (ACT) 后复发感染的宿主。针对休眠寄生虫或保持在治疗水平足够长的时间以杀死恢复中的寄生虫的组合方案可能会提高 ACT 的功效。